Hypersensitivity reaction studies of a polyethoxylated castor oil-free, liposome-based alternative paclitaxel formulation

Abstract

The commercial drug paclitaxel (Taxol) may introduce hypersensitivity reactions associated with the polyethoxylated castor oil-ethanol solvent. To overcome these problems, we developed a polyethoxylated castor oil-free, liposome-based alternative paclitaxel formulation, known as Lipusu. In this study, we performed in vitro and in vivo experiments to compare the safety profiles of Lipusu and Taxol, with special regard to hypersensitivity reactions. First, Swiss mice were used to determine the lethal dosages, and then to evaluate hypersensitivity reactions, followed by histopathological examination and enzyme-linked immunosorbent assays (ELISAs) of serum SC5b-9 and lung histamine. Additionally, healthy human serum was used to analyze in vitro complement activation. Finally, an MTT assay was used to determine the in vitro anti-proliferation activity. Our data clearly showed that Lipusu displayed a much higher safety margin and did not induce hypersensitivity or hypersensitivity-related lung lesions, which may be associated with the fact that Lipusu did not activate complement or increase histamine release in vivo. Moreover, Lipusu did not promote complement activation in healthy human serum in vitro, and demonstrated anti-proliferative activity against human cancer cells, similar to that of Taxol. Therefore, the improved formulation of paclitaxel, which exhibited a much better safety profile and comparable cytotoxic activity to Taxol, may bring a number of benefits to cancer patients.

Preparation and Characterization of Amphiphilic Calixarene Nanoparticles as Delivery Carriers for Paclitaxel

“…Materials Calix [6] arene, calix [8] arene, and PTX were purchased from TCI (Shanghai, China). Ethyl chloroacetate (99%), pyrene (99%), Tween 80 (pharmaceutical grade) were obtained from Aladdin Reagent (Shanghai, China).…”

“…The tetracarboxylic acid of p-tert-butylcalix [4] arene introduced by Ungaro and colleagues was an early example of a water-soluble calixarene. 21) Shinkai et al reported the preparation of p-sulfonato calix [6] arene. 22) Other anionic water-soluble derivatives containing nitro, 23) phosphonic acid, 24) and carboxyl 25) moieties emerged, and the first example of a cationic water-soluble calixarene was reported by Shinkai et al 26) Other cationic calixarenes contain tetraalkylammonium groups and primary amines.…”

“…5) A liposomebased PTX formulation, Lipusu, has been applied for the treatment of ovarian cancer in China. 6) In addition to these approved drugs, a number of PTX nano-DDSs, such as polymeric nanoparticles (NPs), [7][8][9] inorganic NPs, 10) nano-emulsions, 11) carbon nanotubes, 12) and nanogels, 13) have been reported in preclinical studies. Although these novel PTX nano-DDSs exhibit varying levels of success, methods for improving the safety, stability and specificity of nano-DDS still warrant further research.…”

“…The aim of the present work was to develop amphiphilic calixarene carboxylic acid derivatives that can act as a promising nanosize delivery carrier for PTX. For this purpose, two types of calixarene carboxylic acid derivatives, i.e., calix [6] arene hexacarboxylic acid (abbreviated as C 6 HCA) and calix [8] arene octo-carboxylic acid (abbreviated as C 8 OCA), were synthesized and characterized. These calix[n] arene carboxylic acid derivatives (abbreviated as CnCA) formed into nanoparticles using an appropriate method, and their self-assembling ability, particle size, stability, drug loading and release behavior were investigated and compared.…”

Cardio-Oncology

“…Supraventricular arrhythmias, including atrial fibrillation, atrial flutter, and atrial tachycardias, have also occurred with taxanes. 79,81,82 Although the pathogenesis of these arrhythmias may be multifactorial, studies implicate paclitaxel drug delivery vehicle (polyethoxylated castor oil) inducing histamine release as another precipitating factor. 79,81,82 Paclitaxel, similar to colchicine, is microtubule-stabilizing agent, and in normal postmitotic cardiomyocytes, microtubule density is low; thus, taxane agents are not thought to hinder cardiomyocyte contraction.…”